Case Report Novel Therapies for Myocardial Irritability ...downloads.hindawi.com/journals/criem/2015/692948.pdfoverdose. e mortality rate of a CQ overdose for adults is between and

Case ReportNovel Therapies for Myocardial Irritability following ExtremeHydroxychloroquine Toxicity

Paul B. McBeth, Perseus I. Missirlis, Harry Brar, and Vinay Dhingra

Division of Critical Care Medicine, University of British Columbia, Vancouver General Hospital, Vancouver, BC, Canada V5Z 1M9

Correspondence should be addressed to Paul B. McBeth; [email protected]

Received 2 June 2015; Accepted 3 August 2015

Academic Editor: Serdar Kula

Copyright © 2015 Paul B. McBeth et al.This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction. Hydroxychloroquine (HCQ) overdose is rare and potentially deadly when consumed in large doses. Management ofsevere HCQ toxicity is limited and infrequently reported.This report presents the case of a massive ingestion of HCQ. Case Report.A 23-year-old female presents following an intentional ingestion of approximately 40 g ofHCQ.Within six hours after ingestion, shedeveloped severe hemodynamic instability resulting frommyocardial irritabilitywith frequent ventricular ectopic activity leading toruns of polymorphic ventricular tachycardia (PMVT) and ventricular fibrillation (VF) requiringmultiple defibrillations. Additionaltreatments included intravenous diazepam, epinephrine, norepinephrine, sodium bicarbonate, andmagnesium sulfate. Despite theongoing hemodynamic instability, the patient was also treated with Intralipid (ILE) and received hemodialysis. Improvements inher hemodynamics were observed after 18 hours. She survived hermassive overdose ofHCQ.Conclusion. HCQpoisoning is rare butserious because of its rapid progression to life-threatening symptoms. Hemodynamic support, gastric decontamination, electrolytemonitoring and replacement, and management of arrhythmias are the mainstays of treatment. The combined role of dialysis andILE in the setting of massive HCQ overdose may improve outcomes.

1. Introduction

Hydroxychloroquine (HCQ) overdose is rare and often lethalwhen ingested in large doses.There exists a paucity of data onmanagement of HCQ toxicity as it is infrequently reported.Themajority of treatment recommendations are extrapolatedfrom chloroquine (CQ) poising [1, 2]. Current managementstrategies are targeted at myocardial stabilization, hemody-namic support, electrolyte correction, and decontamination[1, 2]. We herein report a unique case of a massive (∼40 g)ingestion of HCQ complicated by coma, hemodynamicinstability, and respiratory failure treated with mechanicalventilation, vasopressor, and inotropic support, as well ashemodialysis and intravenous lipid emulsion (Intralipid)(ILE).

2. Case Presentation

2.1. Clinical Presentation. A 23-year-old female with a pastmedical history of depression, borderline personality dis-order, obsessive compulsive disorder, psychosis NOS, and

congenital hydrocephalus with VP shunt presents followingingestion of approximately 40 g of HCQ. She had beenusing HCQ for the treatment of pruritus. She was alsobeing treated with risperidone, clonazepam, and zopiclonefor her psychiatric disorder and fluconazole at the time ofpresentation for the treatment of a vaginal yeast infection.At presentation, she had a Glasgow Coma Score (GCS):15/15, temperature: 37.1∘C, blood pressure (BP): 92/60mmHg,pulse rate: 65/min, respiratory rate: 16/min, blood glucose:3.9mmol/L, and serum potassium: 3.0mmol/L. The initialblood gas demonstrated a metabolic acidosis and respiratoryalkalosis: pH: 7.33, pCO

2: 16, pO

2: 70, and bicarbonate:

8. Electrocardiograph performed on arrival demonstratedsinus rhythm with a widened QRS (140ms) and QT inter-val (QTc 576ms). See Figure 1. Her urine toxicology wasnegative for salicylates, ethanol, acetaminophen, benzodi-azepines, cannabinoid, cocaine, opiates, and amphetamines.The presenting renal and hepatic laboratory values areas follows: creatinine (Cr): 133 𝜇mol/L; albumin: 39 g/L;lipase: 113 units/L; gamma-glutamyl transpeptidase (GGT):30 units/L; alkaline phosphatase: 55 units/L; total bilirubin:

Hindawi Publishing CorporationCase Reports in Emergency MedicineVolume 2015, Article ID 692948, 4 pageshttp://dx.doi.org/10.1155/2015/692948

2 Case Reports in Emergency Medicine

Figure 1: Presenting ECG tracing.

3 𝜇mol/L; direct bilirubin: 1 𝜇mol/L; alanine aminotrans-ferase (ALT): 23 units/L; aspartate aminotransferase (AST):14 units/L.

2.2. Resuscitation and Management. Within three hoursof her overdose, the patient became obtunded requiringintubation and mechanical ventilation. Hypotension wastreated with crystalloid and vasopressor support. Gastriclavage and activated charcoal for decontamination wereprovided.Within six hours of her overdose, she demonstratedsevere hemodynamic instability resulting from myocardialirritability with frequent ventricular ectopic activity leadingto runs of polymorphic ventricular tachycardia (PMVT) andventricular fibrillation (VF) requiring 18 defibrillations with200J with biphasic defibrillator over the first 18 hours afteringestion. Given her protracted cardiac instability, additionaltreatments including intravenous diazepam 60mg followedby infusion of 6mg/hr for calcium channel stabilization (totalof 82mg given), epinephrine 20mcg/min, norepinephrine30mcg/min, sodium bicarbonate 30mmol/hr, and magne-sium sulfate 1 g/hr infusions were also initiated. The serumpotassium three hours after the overdose was 1.5mmol/L. Intotal, 380mmol of potassium chloride was given over the first18 hours administered in 20mmol boluses. She also receivedintravenous sodium bicarbonate for alkalization. To treatrefractory ventricular ectopy, a bolus dose of 1.5mL/kg of20% Intralipid ILE was initially given followed by a high doseinfusion over approximately 30 minutes. A total of 500mLof ILE was given. No further infusion of ILE was given afterthis initial dose. Vascular access for dialysis was establishedimmediately after the bolus dose and thus dialysis overlappedbriefly with the infusion of ILE. The runs of PMVT and VFwere felt to be secondary to a preexisting channelopathy likelypotentiated by fluconazole and risperidone. Ventricular pac-ing was reviewed but not considered indicated. The patientwas started on piperacillin/tazobactam for possible aspirationpneumonia. Echocardiographic imaging revealed normalglobal ventricular contractility with an ejection fraction of60%.

The patient was started on intermittent hemodialysis(IHD) in an attempt to reduce HCQ levels despite a paucityof literature regarding its use.The pharmacokinetics suggeststhat much of the drug is not accessible to the dialyzer,but given the severity of the overdose and the impact ofhemodynamics even a small amount removedwas consideredfavorable. Plasma HCQ level was 6425mol/L 12 hours afteringestion. A five-hour run of hemodialysis was initiatedwith end points being either improved hemodynamics or ofsignificant decrease in blood levels. A F1000 Dialyzer wasused with a dialysate flow rate of 800 cc/hr. In total, 135 L ofblood was processed. As noted above, concurrent with thedialysis run, an ILE infusion was administered in an effort to

create a “lipid sink” to sequester lipophilic HCQ. At 31 hoursafter ingestion, the plasma HCQ level was 4328mol/L.

Improvements in her hemodynamics were observed afteradministration of dialysis and ILE. She was subsequentlyweaned from the ventilator and extubated on day 3 anddischarged from ICU on postadmission day six.

3. Discussion

Hydroxychloroquine is sold under the trade name Plaqueniland is an aminoquinoline derivative used in the prophy-laxis and treatment of malaria. It is also used as an anti-inflammatory agent in rheumatoid arthritis and complica-tions of lupus and connective tissue disorders with an offlabel use in the treatment of urticaria. Hydroxychloroquine ishighly toxic in overdose resulting in rapid onset of hypoten-sion, ventricular dysrhythmias, and cardiac arrest resulting indeath [1–3]. Seizures, coma, and respiratory arrest can occurin patients with severe toxicity [3].

Descriptions of HCQ overdose are limited to case reportsin the literature. Given this paucity of data, the currentemergency treatment is modeled on the experience of CQoverdose. The mortality rate of a CQ overdose for adultsis between 10 and 30% [1]. Unlike a CQ overdose, there isno established lethal or toxic dose of HCQ. Treatments aretargeted at myocardial stabilization, hemodynamic support,electrolyte correction, decontamination, and prevention ofseizures. At present, there is limited data regarding the use ofdialysis and to our knowledge there is no description of theuse of ILE in combination with dialysis.

Hydroxychloroquine has a dose-related cardiac sodiumand potassium channel blocking effect resulting in delayedrepolarization and slow intraventricular conduction. Thisresults in bradycardia, hypotension, ventricular dysrhyth-mias, widened QRS, and prolonged QT interval [4].Hypokalemia appears to be due to intracellular movement ofpotassium via a direct effect on cell membrane.

Hydroxychloroquine is rapidly absorbed following inges-tion. Peak plasma levels of HCQ occurred 2–4.5 hoursafter ingestion. In overdose, onset of symptoms usuallyoccurs within 30 minutes. It is highly tissue bound witha large volume of distribution. Distributional half-life is15–30 hours [5]. Elimination half-life ranges from 4 to 40days. Death from cardiorespiratory arrest or refractory shockoften occurs within 3 hours after ingestion. ECG changesinclude QRS widening and QT prolongation [3, 6]. Commondysrhythmias include ventricular ectopic beats, ventriculartachycardia, ventricular fibrillation, and torsades de pointes.

Patients presenting to health care facilities less than one-hour after ingestion should be considered for gastric decon-taminationwith gastric lavage and activated charcoal.Theuseof multiple-dose activated charcoal should be considered insevere HCQ poisoning [7, 8].

Profound hypokalemia is a known effect of HCQ poison-ing and appears to correlate with toxicity. The mechanismis related to reduced potassium efflux from the blockade ofmembrane channels. It is unknown whether HCQ causesdirect cardiotoxicity or if it is partly due to the hypokalemia.

Case Reports in Emergency Medicine 3

ECG findings include prolonged QT and QRS intervals lead-ing to life-threatening ventricular arrhythmias and cardiacarrest [3, 6]. Aggressive potassium replacement is required;however, monitoring for rebound hyperkalemia [9–11] withresultant dysrhythmias is important. Diazepam infusion (1-2mg/kg IV over 30 minutes) has been suggested to modifycardiac toxicity and improve survival based on animal experi-mental data [4, 12].This has also been demonstrated in severalretrospective studies in patients with acute HCQ toxicity [12–14]. The chronic use of HCQ may lead to QT prolongation[15]. Physicians prescribingHCQ to patients for extended useshould consider monitoring patients for cardiac arrhythmias.

The clinical value of hemodialysis and peritoneal dialysishas not been established for the overdose of HCQ. Theapparent volume of distribution for HCQ is approximately600 L/kg.This implies that the drug rapidly becomes unavail-able for removal after ingestion [1]. The extensive sequestra-tion of HCQ by tissues limits effectiveness of hemodialysis.Despite the lack of guidelines in favor of hemodialysis in thiscase, it may have been helpful for the following reasons. CQand by extensionHCQ are known to interfere with potassiumefflux and facilitate insulin release [16]. Hypokalemia andhypoglycemia are both known precipitants of cardiac arrest.Perhaps critical hypokalemia and hypoglycemia were avertedby stabilizing plasma levels with hemodialysis. Secondly,in the face of the overwhelming overdose, the “lipid sink”provided by ILE may become saturated and thus abolish thegradient for lipophilic compounds to diffuse out from theintracellular compartment to the extracellular compartment.It is conceivable that the “lipid sink” diffusion gradient waspreserved by dialysing Intralipid that had become saturatedwith HCQ. Extracorporeal membrane oxygenation (ECMO)has also been successfully demonstrated in an isolated casesevere HCG toxicity [17]. The use of ECMO was not consid-ered in this case.

Intravenous lipid emulsion is commercially available andtermed Intralipid for treatment of local anesthetic systemictoxicity (LAST). Early basic science research by Weinberg etal. established that lipid emulsion successfully resuscitatedrats and dogs from bupivacaine induced cardiac arrest [18,19]. This work described the “lipid sink” theory of ILE,whereas ILE may act as an expanded lipid reservoir tosequester lipophilic bupivacaine away from cardiac myocytes[18]. Rosenblatt et al. described the first use of ILE for thetreatment of cardiac arrest after bupivacaine andmepivacaineoverdose [20]. Subsequently, Litz et al. reported the recoveryof a perfusing cardiac rhythm with ILE after prolongedasystolic arrest following a ropivacaine overdose after axillaryplexus block [21]. Given these promising developments, therole of ILE was expanded from the treatment of LAST toother toxic overdoses [17, 22]. Similar to bupivacaine, HCQis lipophilic with a large volume of distribution [23] andblocks sodium channel function [24]. Experience with HCQoverdose is limited as there are few published case reportsin the literature. Thus, resuscitation of HCQ overdose ismanaged similar to CQ overdose given their structural andtoxidromal similarities [1]. A recent case report describestwo cases of HCQ overdose in which ILE was utilized in theresuscitation [25]. Despite the standard resuscitation of these

patients with sodium bicarbonate and diazepam, both dieddespite ILE infusion. The first case was a mixed overdose ofHCQ and CQ in which the patient developed torsades despointes that failed to respond to single bolus dose of 100mLof 20% Intralipid. The second patient suffered from a cardiacarrest following a 20mg HCQ overdose with the returnof spontaneous circulation (ROSC) after cardiopulmonaryresuscitation (CPR) for 5 minutes. A bolus dose of 100mLof 10 Intralipid was given followed by 400mL over 30minutes. The patient subsequently developed wide complextachycardia and cardiac arrest with ROSC after 25 minutesof CPR. Despite these interventions, the patient sufferedanother arrest and died. In both cases, the authors did notinstitute hemodialysis.

4. Conclusion

In conclusion, HCQ poisoning is rare but serious because ofits rapid progression to life-threatening symptoms. Hemody-namic support, gastric decontamination, electrolytemonitor-ing and replacement, andmanagement of arrhythmias are themainstays of treatment. The combined role of dialysis andILE in the setting of massive HCQ overdose may improveoutcomes by extending the “lipid sink” effect of ILE andnormalizing electrolyte concentrations.

Conflict of Interests

The authors declare that there is no conflict of interests.

Authors’ Contribution

Paul B. McBeth, Perseus I. Missirlis, and Harry Brar weremajor contributors in writing the paper, providing the revi-sions, and creating the figures. Paul B. McBeth, Harry Brar,Perseus I. Missirlis, and Vinay Dhingra provided revisionsand contributed to the writing and completion of the paper.Vinay Dhingra provided critical revisions and gave finalapproval of the version for publication. All the contributingauthors have read and approved the final paper.

References

[1] K. Marquardt and T. E. Albertson, “Treatment of hydroxy-chloroquine overdose,” American Journal of EmergencyMedicine, vol. 19, no. 5, pp. 420–424, 2001.

[2] P. Jordan, J. G. Brookes, G. Nikolic, and D. G. Le Counteur,“Hydroxycholoroquine overdose: toxicokinetics and manage-ment,” Journal of Toxicology. Clinical toxicology, vol. 37, no. 7,pp. 861–864, 1997.

[3] G. K. Isbister, A. Dawson, and I. M. Whyte, “Hydroxychloro-quine overdose: a prospective case series,” American Journal ofEmergency Medicine, vol. 20, no. 4, pp. 377–378, 2002.

[4] S. A. Pruchnicki, T. F. Good, and P. D. Walson, “Severe hydrox-ychloroquine poisoning reversed with diazepam,” Journal ofToxicology. Clinical Toxicology, vol. 33, p. 582, 1996.

[5] D. N. Bateman, P. G. Blain, K. W. Woodhouse et al., “Phar-macokinetics and clinical toxicity of quinine overdosage: lack

4 Case Reports in Emergency Medicine

of efficacy of techniques intended to enhance elimination,”Quarterly Journal of Medicine, vol. 54, no. 214, pp. 125–131, 1985.

[6] J.-L. Clemessy, C. Favier, S. W. Borron, P. E. Hantson, E. Vicaut,and F. J. Baud, “Hypokalaemia related to acute chloroquineingestion,”The Lancet, vol. 346, no. 8979, pp. 877–880, 1995.

[7] D. Lockey and D. N. Bateman, “Effect of oral activated charcoalon quinine elimination,” British Journal of Clinical Pharmacol-ogy, vol. 27, no. 1, pp. 92–94, 1989.

[8] L. F. Prescott, A. R. Hamilton, and R. Heyworth, “Treatment ofquinine overdosage with repeated oral charcoal,” British Journalof Clinical Pharmacology, vol. 27, no. 1, pp. 95–97, 1989.

[9] A. Jaeger, P. Sauder, J. Kopferschmitt, and F. Flesch, “Clinicalfeatures and management of poisoning due to antimalarialdrugs,”Medical Toxicology and Adverse Drug Experience, vol. 2,no. 4, pp. 242–273, 1987.

[10] J.-L. Clemessy, P. Taboulet, J. R. Hoffman et al., “Treatment ofacute chloroquine poisoning: a 5-year experience,” Critical CareMedicine, vol. 24, no. 7, pp. 1189–1195, 1996.

[11] J. L. Clemessy, S. W. Borron, and F. J. Baud, “Hypokalaemia andacute chloroquine ingestion—reply,” The Lancet, vol. 347, no.8998, pp. 404–405, 1996.

[12] J. L. Crouzette, E. Vicaut, S. Palombo, C. Girre, and P. E.Fournier, “Experimental assessment of the protective activityof diazepam on the acute toxicity of chloroquine,” Journal ofToxicology: Clinical Toxicology, vol. 20, no. 3, pp. 271–279, 1983.

[13] J. Demaziere, J. M. Saissy, M. Vitris et al., “Effects of diazepamon mortality from acute chloroquine poisoning,” AnnalesFrancaises d’Anesthesie et de Reanimation, vol. 11, no. 2, pp. 164–167, 1992.

[14] J. Crouzette, E. Vicaut, S. Palombo, C. Girre, and P. E. Fournier,“Experimental assessment of the protective activity of diazepamon the acute toxicity of chloroquine,” Journal of Toxicology:Clinical Toxicology, vol. 20, no. 3, pp. 271–279, 1983.

[15] F. Mongenot, Y. Tessier Gonthier, F. Derderian, M. Durand,and D. Blin, “Treatment of hydroxychloroquine poisoning withextracorporeal circulation,”Annales Francaises d’Anesthesie et deReanimation, vol. 26, no. 2, pp. 164–167, 2007.

[16] C.-Y. Chen, F.-L. Wang, and C.-C. Lin, “Chronic hydroxy-chloroquine use associated with QT prolongation and refrac-tory ventricular arrhythmia,” Clinical Toxicology, vol. 44, no. 2,pp. 173–175, 2006.

[17] L. Rothschild, S. Bern, S. Oswald, and G. Weinberg, “Intra-venous lipid emulsion in clinical toxicology,” ScandinavianJournal of Trauma, Resuscitation and Emergency Medicine, vol.18, no. 1, article 51, 2010.

[18] G. L.Weinberg, T. VadeBoncouer, G. A. Ramaraju,M. F. Garcia-Amaro, and M. J. Cwik, “Pretreatment or resuscitation with alipid infusion shifts the dose-response to bupivacaine-inducedasystole in rats,” Anesthesiology, vol. 88, no. 4, pp. 1071–1075,1998.

[19] G.Weinberg, R. Ripper, D. L. Feinstein, andW.Hoffman, “Lipidemulsion infusion rescues dogs from bupivacaine-inducedcardiac toxicity,” Regional Anesthesia and PainMedicine, vol. 28,no. 3, pp. 198–202, 2003.

[20] M.A. Rosenblatt,M.Abel, G.W. Fischer, C. J. Itzkovich, and J. B.Eisenkraft, “Successful use of a 20% lipid emulsion to resuscitatea patient after a presumed bupivacaine-related cardiac arrest,”Anesthesiology, vol. 105, no. 1, pp. 217–218, 2006.

[21] R. J. Litz, M. Popp, S. N. Stehr, and T. Koch, “Successfulresuscitation of a patient with ropivacaine-induced asystoleafter axillary plexus block using lipid infusion,”Anaesthesia, vol.61, no. 8, pp. 800–801, 2006.

[22] A. J. Sirianni, K. C. Osterhoudt, D. P. Calello et al., “Use of lipidemulsion in the resuscitation of a patientwith prolonged cardio-vascular collapse after overdose of bupropion and lamotrigine,”Annals of Emergency Medicine, vol. 51, no. 4, pp. 412.e1–415.e1,2008.

[23] H.-S. Lim, J.-S. Im, J.-Y. Cho et al., “Pharmacokinetics ofhydroxychloroquine and its clinical implications in chemo-prophylaxis against malaria caused by Plasmodium vivax,”Antimicrobial Agents andChemotherapy, vol. 53, no. 4, pp. 1468–1475, 2009.

[24] P. F. Kolecki and S. C. Curry, “Poisoning by sodium channelblocking agents,” Critical Care Clinics, vol. 13, no. 4, pp. 829–848, 1997.

[25] O. F. Wong, Y. C. Chan, S. K. Lam, H. T. Fung, and J. K. Y. Ho,“Clinical experience in the use of intravenous lipid emulsion inhydroychloroquine and chloroquine overdose with refractoryshock,”Hong Kong Journal of EmergencyMedicine, vol. 18, no. 4,pp. 243–248, 2011.

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Case Report Novel Therapies for Myocardial Irritability ...downloads.hindawi.com/journals/criem/2015/692948.pdfoverdose. e mortality rate of a CQ overdose for adults is between and